The proposed studies in this application focus on the systematic elucidation of the mechanistic role of lymphocytes and lymphokines in lymphocyte/macrophage/foreign body giant cell interactions in the foreign body response to biomedical polymers. Our working hypothesis is that lymphokine-mediated macrophage activation, direct lymphocyte/macrophage interaction, and lymphokine-induced foreign body giant cell (FBGC) formation on biomaterials are the result of complex extracellular and intracellular mechanisms that can be controlled by biomaterial surface chemistry. In the proposed studies, we will elucidate the specific role of lymphocytes and lymphokines in lymphocyte/macrophage interactions in the foreign body response, both in vitro and in vivo, using a series of well-characterized surface modified materials. These studies will focus on how direct (cell/cell) and indirect (cell/cytokine) interactions lead to monocyte/macrophage activation, lymphocyte activation and proliferation, macrophage fusion into FBGC, giant cell-mediated biomaterial degradation, and the generation of humoral (antibody) and cellular (B and T lymphocytes) responses upon secondary exposure to the biomaterial. Emphasis will be placed on our previously established and well-characterized in vitro human monocyte/macrophage culture system, which has been expanded to include co-cultures of autologous lymphocyte populations under carefully controlled in vitro conditions. In vitro findings will be correlated to and validated by the in vivo environment through established mouse cage and subcutaneous implant systems. In vitro and in vivo analyses will use state-of-the-art methods, including: cell proliferation assays, enzyme-linked immunosorbent assays (ELISA), flow cytometry, and fluorescence activated cell sorting (FACS), fluorescence confocal laser scanning microscopy (FCLSM), immunohistochemistry, optical microscopy, semi-quantitative reverse transcription polymerase chain reaction, and several other cellular and molecular-based assays. Results from studies addressing the hypothesis and four specific aims will be used to identify complex cell/material interactions and lead to novel design criteria for new biomaterials and tissue-engineered surfaces.